The present invention relates to novel enkephalin derivatives. In particular, it provides novel enkephalin derivatives of formula I which are useful as analgesic agents.
In 1975, a pentapeptide, methionine enkephalin, was reported by Hughes et. al. Nature, 258, p.577 (1975). This peptide is found in many areas of the brain where it appears to act as a neurotransmitter or neuromodulator in a central painsuppressant system. The natural peptide binds sterospecifically to partially purified brain opiate receptor sites, see for example, Bradberry et. al., Nature 260, p.793 (1976). The natural peptide is also highly active in bioassays for opiate activity but exhibits only weak, fleeting analgesic activity when injected directly into the brain of the rat, see for example, Belluzi et. al., Nature, 260, 625 (1976).
In order to overcome the lack of in vivo activity, a number of investigators have made numerous modifications in the methionine enkephalin structure, such as substituting the glycine in the 2-position with a D-amino acid, N-methylation of the 1-tyrosine; substituting the 4-phenylalanine with, for example, methyl or halo; modifying the C-terminus, etc. to produce enkephalin derivatives of varying properties and potencies. The present invention provides new enkephalin derivatives which approach the potency of morphine as analgesic agents by both oral and parenteral routes of administration.